Official Journal of the Brazilian Psychiatric Association Volume 34 • Number 2 • June/2012
Psychiatry
Revista Brasileira de Psiquiatria
Abstract
Objective: To report structural and functional neuroimaging studies exploring the potential role of the orbitofrontal cortex (OFC) in the pathophysiology of the most prevalent psychiatric disorders (PD). Method: A non-systematic literature review was conducted by means of MEDLINE using the following terms as parameters: “orbitofrontal cortex”, “schizophrenia”, “bipolar disorder”, “major depression”, “anxiety disorders”, “personality disorders” and “drug addiction”. The electronic search was done up to July 2011. Discussion: Structural and functional OFC abnormalities have been reported in many PD, namely schizophrenia, mood disorders, anxiety disorders, personality disorders and drug addiction. Structural magnetic resonance imaging studies have reported reduced OFC volume in patients with schizophrenia, mood disorders, PTSD, panic disorder, cluster B personality disorders and drug addiction. Furthermore, functional magnetic resonance imaging studies using cognitive paradigms have shown impaired OFC activity in all PD listed above. Conclusion: Neuroimaging studies have observed an important OFC involvement in
a number of PD. However, future studies are clearly needed to characterize the speciic role of
OFC on each PD as well as understanding its role in both normal and pathological behavior, mood regulation and cognitive functioning.
The involvement of the orbitofrontal cortex in psychiatric
disorders: an update of neuroimaging indings
Andrea Parolin Jackowski,
1Gerardo Maria de Araújo Filho,
1Amanda Galvão de Almeida,
1,2Célia Maria de Araújo,
1Marília Reis,
1Fabiana Nery,
1,2Ilza Rosa Batista,
1Ivaldo Silva,
1Acioly L. T. Lacerda
1,3,41 Laboratório Interdisciplinar de Neurociências Clínicas (Interdisciplinary Laboratory of Neurosciences - LiNC), Universidade Federal de São Paulo, São Paulo, Brazil
2 Affective Disorders Center, Universidade Federal da Bahia (UFBA), Salvador, Brazil 3 Instituto Sinapse de Neurociências Clínicas, Campinas, São Paulo, Brazil
4 Centro de Pesquisa e Ensaios Clínicos Sinapse-Bairral. Itapira, São Paulo, Brazil
Received on October 3, 2011; accepted on February 17, 2012 UPDATE ARTICLE
Corresponding author: Andrea P. Jackowski. Rua Pedro de Toledo 669, 3o. Andar fundos. São Paulo, SP, Brazil. 04039-032. Phone/fax: (+55 11) 50847060. E-mail: andrea.jackowski@gmail.com
1516-4446 - ©2012 Elsevier Editora Ltda. All rights reserved. DESCRIPTORS
O envolvimento do cortex orbitofrontal em transtornos psiquiátricos: uma atualização dos achados de neuroimagens
RESUMO
Objetivo: Relatar estudos de neuroimagens estruturais e funcionais explorando o papel potencial
do córtex orbitofrontal (COF) na isiopatologia dos transtornos psiquiátricos (TP) mais prevalen -tes. Método: Foi realizada uma revisão não sistemática da literatura no MEDLINE, usando como
parâ metros os seguintes termos: “córtex orbitofrontal”, “esquizofrenia”, “transtorno bipolar”, “depressão maior”, “transtornos ansiosos”, “transtornos de personalidade” e “dependência a dro-gas”. A pesquisa eletrônica foi feita até julho de 2011. Discussão: Foram relatadas anormalidades estruturais e funcionais do COF em muitos TP, particularmente esquizofrenia, transtornos afetivos, transtornos ansiosos, transtornos de personalidade e dependência a drogas. Estudos de aquisição de imagens estruturais por ressonância magnética relataram a redução do volume do COF em pacientes portadores de esquizofrenia, transtornos afetivos, TEPT, transtorno do pânico, trans-tornos de personalidade do grupo B e dependência a drogas. Além disso, estudos de aquisição de imagens funcionais por ressonância magnética empregando paradigmas cognitivos demonstraram alterações na atividade do COF em todos os TP anteriormente relacionados. Conclusão: Estudos de
neuroimagens observaram um envolvimento importante do COF em vários TP. Entretanto, estudos futuros são claramente necessários para caracterizar o papel especíico do COF em cada TP, assim
como para a compreensão de seu papel tanto no comportamento normal como no patológico, na regulação do humor e no funcionamento cognitivo.
Introduction
The frontal lobe has been implicated in a number of psychiat-ric disorders (PD) including depression, anxiety and psychotic disorders.1,2 The orbitofrontal cortex (OFC) - a subdivision of the prefrontal cortex (PFC) - is connected to neuroanatomical structures directly involved in the emotional and executive processing, such as the hippocampal formation, amygdala, ventral striatum, anterior cingulated, hypothalamus and medial temporal areas.3,4 The OFC has been associated with adaptive behavior in the face of changing contingencies and unexpected outcomes, reward-guided behavior and decision making.1,2 In addition, neuropsychological studies have also observed an association between OFC lesions with socioemo-tional disinhibition and executive dysfunctions.5,6
Converging indings from structural and functional neuro -imaging, neuropsychology and neurophysiology studies indicate that the human OFC plays an important role in the development of psychiatric disorders (PD) such as schizophrenia, mood and anxiety disorders, personality disorders and drug addiction.3 In this article, the available structural and functional neuroimaging studies that investigated OFC involvement in the most prevalent PD in clinical practice, such as schizophrenia, mood disorders (major depression and bipolar disorder), anxiety disorders (post-traumatic stress disorder, phobias, and obsessive-compulsive disorder), personality disorders, and substance abuse were reviewed in order to provide an update to clinicians of the trans-lational research involving the possible role of OFC in such PD.
Methods
The authors searched the database of PubMed from January 1980 to July 2011 for the published English-language stud-ies on investigation of OFC involvement in most common PD
through structural and/or functional neuroimaging methods. The search terms used as parameters were: “orbitofrontal cortex”, “schizophrenia”, “bipolar disorder”, “major depres-sion”, “anxiety disorders”, “personality disorders” and “drug addiction”. The inclusion criteria were: 1) structural and/or functional neuroimaging studies investigating the role of OFC in those referred PD; 2) presence of a control group (healthy or with other PD); 3) absence of comorbid PD. Although studies with drug-naïve patients were more present in lit-erature, aiming to exclude the effect of psychotropic drugs in neuroimaging, studies which involved patients under the inluence of psychotropic drugs were not excluded.
Results
A brief summary of indings of all neuroimaging studies in -cluded is shown in Table 1.
Psychiatric Disorders
Schizophrenia
Schizophrenia is one of the most severe and debilitating psychiatric disorders, affecting 0.5%-1.5% of the adult population worldwide. Although the pathophysiology of such disorder remains unclear, studies have consistently suggested an involvement of biological and environmental factors.7,8 Frontal lobe changes have been considered one of the main characteristics of schizophrenia. The deicits observed in attention, working memory, reasoning and problem solving have been recognized as a fundamental component of the disorder.8
Structural and functional MRI studies have been per-formed in patients with schizophrenia. Venkatasubramanian et al.9 reported signiicant volume reductions in left medial and in right and left lateral OFC among antipsychotic-naïve patients with schizophrenia. However, another study showed an increase of the left total and lateral OFC volumes in drug-naïve patients with schizophrenia in comparison to healthy controls, correlating those indings with negative symptoms.10 Functional magnetic resonance imaging (fMRI) studies have demonstrated altered medial OFC, the amyg-dala and insula activation during social decision-making in schizophrenia patients.11,12 In addition, increased left OFC and medial frontal gyrus activation in adolescent-onset schizophrenia compared with controls subjects have also been reported. 12
Mood Disorders
Major depression
Most recent studies have highlighted that a combination of genetic, psychological, and environmental factors contribute to the onset of Major Depression.13-15 Structural neuroimaging studies have observed reductions of OFC volumes among MDD individuals. In a MRI study performed in 31 unmedicated MDD and in gender-matched healthy subjects age 34, smaller gray matter volumes in right medial and left lateral OFC were observed among MDD individuals. Left lateral OFC volume was
negatively correlated with age in patients but not in control subjects.13 However, other studies failed to ind differences of OFC volume in depressed individuals.14
Regarding functional studies, Drevets15 synthesized the main evidences observed in OFC of MDD individuals: increased glucose metabolism/cerebral blood low (CBF) in medial and lateral OFC in depressed versus remitted phase and decreased CBF in medial OFC in remitted phase. In addition, a reduction of 5-HT 1A receptor binding in OFC was observed.15
Bipolar disorder
The essential feature of Bipolar Disorder (BD) is a clinical course with the occurrence of major depressive episodes and manic or hippomanic episodes.7 There is evidence that OFC volume may be reduced in adolescents and adults with bipolar disorder, and that the rostral and lateral OFC subregions have reduced activation during manic episodes.16 Furthermore, it has been shown that OFC activation is attenuated in depressed bipolar subjects.16 However, other studies examined volumetric measures of the whole brain and prefrontal cortices where no consistent differences were found between BD and controls.16,17
Anxiety Disorders
Posttraumatic Stress Disorder (PTSD)
PTSD is characterized by the development of anxiety symp-toms and avoidance behavior after exposure to a traumatic external stressor.7 Hakamata et al.18 observed reductions of
Table 1 Involvement of orbitofrontal cortex in psychiatric disorders: summary of indings of neuroimaging studies.
Psychiatric disorder
Author, year Imaging method and postprocessing technique
N# of patients
Control group
Results in patients
Schizophrenia Lacerda et al.10 Structural – ROI 43 53 healthy ↑OFC volume
Schizophrenia Waltz et al.12 Functional – fMRI 36 24 healthy ↓OFC activation
Schizophrenia Venkatasubramanian et al.9 Structural – MRI ROI 51 47 healthy ↓OFC volume & thickness
Schizophrenia Bass et al.11 Functional – fMRI 12 21 healthy ↓OFC, amygdale and insula activation
MDD Lacerda et al.13 Structural – ROI 31 34 healthy ↓OFC volume
Bipolar Disorder Altshuler et al.17 Functional – fMRI 11 17 healthy ↓OFC activation
PTSD Hakamata et al.18 Structural – VBM 9 67 without PTSD ↓OFC volume
PTSD Shin et al.19 Functional – PET 16 8 healthy ↑CBF in OFC
PTSD Shin et al.20 Functional – PET 17 19 healthy ↑CBF in OFC
Panic Disorder Roppongi et al.21 Structural – VBM 28 28 healthy ↓OFC volume
Panic Disorder Kent et al.22 Functional – PET 5 5 healthy ↓CBF in OFC
OCD Rauch et al.23 Functional – fMRI 12 12 healthy ↑OFC activation
OCD versus MDD Remijnse et al.24 Functional – fMRI 20 20 MDD / 27 healthy ↑OFC activation in OCD
BPD Chanen et al.25 Structural – ROI 20 20 healthy ↓OFC volume
BPD Silbersweig et al.27 Functional – fMRI 16 14 healthy ↓OFC activation
SUD Tanabe et al.28 Structural – VBM 19 20 ↓OFC volume
SUD Alia-Klein et al.29 Structural – ROI 40 42 ↓OFC volume
BPD: borderline personality disorder; CBF: cerebral blood low; fMRI: functional magnetic resonance imaging; MDD: major depressive disorder; MRI:
OFC volumes in survivors of cancer with PTSD when they were compared to cancer survivors without PTSD and to a healthy group control. These results suggest that these alterations might result in a failure of the OFC in inhibiting an exag-gerated fear response of the amygdala which could explain some of the intrusive symptoms observed in PTSD subjects.18
Functional neuroimaging studies have been conducted to elucidate the neurocircuitry involved in the complex symptomatology of PTSD. Shin et al. 19, in a Positron Emission Tomography (PET) study, compared two women groups with history of childhood sexual abuse, but only one group with PTSD. There was an increase in OFC rCBF during traumatic im-agery exposure in both groups, but such increase was greater in the PTSD group.19 Shin et al. 20 compared a PTSD and a non-PTSD group of Vietnam veterans. Both groups were exposed to neutral and traumatic events (scripts tape-recorded with autobiographic events of the participants) during PET scan. Signiicant rCBF reductions in OFC and middle frontal gyrus were observed in the PTSD group during traumatic exposure; those reductions were negatively correlated to rCBF in the left amygdala and right periamygdaloid cortex.20
Panic Disorder
Although there are few studies that evaluated OFC volume and morphology in PanD, a recent study evaluated the anatomical pattern of the posterior orbital sulcus and the OFC volume using the MRI of 28 patients with PanD and gender-matched healthy controls age 28, observing right posterior-medial OFC reductions among PanD individuals.21 In a PET study with a panic provocation protocol, reduced rCBF in the OFC was observed in the right OFC in a single case during an unexpected panic attack.22
Obsessive Compulsive Disorder
Neuroimaging studies have suggested cortico-striatum-thal-amo-cortical circuitry involvement in the pathophysiology of OCD. In fact, OFC hyperactivity in OCD seems to be due to an impairment of thalamic regions.23 Studies involving fMRI have demonstrated a deviant activation in the OFC in OCD patients during a serial reaction time task and in symptom provocation paradigm studies.23,24 A recent fMRI study showed blunted responsiveness in the OFC of patients with OCD dur-ing a self-paced reversal learndur-ing task which corroborates with previous indings.24
Personality Disorders
Based on the main personality characteristics, the DSM-IV classiies the personality into three clusters: A – excentric (paranoid, schizoid and schizotypical); B – with marked impulsivity and dificulty to accept social rules (antisocial, borderline, narcisistic and hystrionic); and C – anxious and risk-avoidant.7 Literature data have suggested a critical role of OFC particularly in cluster B personality disorders, clini-cally characterized by a marked impulsivity, unsteadiness, mood reactivity, emotional instability and dificulty to accept social rules.7,25 Structural MRI studies have demonstrated decreased OFC volumes in patients with borderline and antisocial personality disorders, suggesting a possible role of this region, added to other frontolimbic structures such as the anterior cingulate, amygdala and hippocampus in the development of cluster B symptoms.25
Studies involving fMRI observed an impaired inhibitory function of OFC in borderline personality disorders when patients were exposed to negative emotions.26,27 Therefore,
neuroimaging indings of structural and functional alterations in OFC observed mainly in patients with cluster B personal-ity disorders are in agreement with the critical role of such structure, which is involved in the regulation of mood reac-tivity and impulsivity.25-27
Drug Addiction
Substance use disorders (SUDs) are characterized by a com-pulsion to seek and take the drug and a loss of control in limiting intake.7 It is postulated that the OFC is involved in drug addiction due to indirect and direct connections to brain areas known to be involved with: (a) reinforcing effects of drug abuse; (b) motivation and compulsive behaviors; and (c) other brain areas related to reward processing (striatum-thalamus-orbitofrontal circuitry).28,29
Most of imaging studies in addiction have used PET and SPECT with multiple radiotracers to detect and measure changes in Dopamine (DA), the most important neurotrans-mitter involved in addiction in the human brain. In a PET ra-diotracer [F18] luoro-deoxyglucose (FDG) study, a signiicant decrease in OFC activity was found in alcohol, cocaine, crack and marihuana users.30 The reduced activity was associated with decreased availability of D2 DA receptors in striatum.30,31 A 99mTc-hexametazine (HMPAO) SPECT study involving chronic use of opiates has demonstrated decrease in global brain perfusion abnormalities more signiicant in OFC.30,31
Conclusion
The OFC plays a central role in humanbehavior. It is con-nected to association areas of allsensory modalities, limbic structures, and prefrontal cortical regionsthat mediate executive function, including control and inhibition of in-appropriate behavioral and emotional responses, decision making, maintaining behavioral lexibility to switch between different problem solving strategies, and evaluation of con-tingencies between different stimuli.1-6 The main aim of such non-systematic revision was to provide an update to clinicians of the translational research involving the participation of OFC in most common PD. These observations have a clinical relevance since they could help in the comprehension of the pathophysiology of psychiatric symptoms and disorders, as well as in the development of treatment strategies. Although functional and structural neuroimaging studies have pro-vided evidence of OFC impairment in PD, characterizing the role of OFC in each PD is complicated by multiple factors. These include differences in underlying pathophysiology of PD and heterogeneity in function across different OFC sub-territories. Therefore, additional neuroimaging studies are necessary to understand and discriminate such aspects.
Disclosures
Andrea Parolin Jackowski
Gerardo Maria de Araújo Filho
Employment: São Paulo Association for Medicine Development (Associação Paulista para o Desenvolvimento da Medicina - SPDM), Brazil. Research grant: National Counsel of Technological and Scientiic Development (Conselho Nacional de Desenvolvimento Cientíico e Tecnológico - CNPq)*,
Brazil. Other: Laboratório Interdisciplinar de Neurociências Clínicas
(LiNC), UNIFESP, Brazil. Amanda Galvão de Almeida
Other: Laboratório Interdisciplinar de Neurociências Clínicas (LiNC),
UNIFESP; Affective Disorders Center, UFBA, Brazil. Célia Maria de Araújo
Employment: São Paulo Association for Medicine Development (Associação Paulista para o Desenvolvimento da Medicina - SPDM); Universidade Federal de São Paulo (UNIFESP), Brazil. Other: Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), UNIFESP, Brazil. Marília Reis
Other:Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), UNIFESP, Brazil.
Fabiana Nery
Other: Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), UNIFESP; Affective Disorders Center, UFBA, Brazil.
Ilza Rosa Batista
Other:Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), UNIFESP, Brazil.
Ivaldo Silva
Employment: Universidade Federal de São Paulo (UNIFESP), Brazil. Other:Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), UNIFESP, Brazil.
Acioly L. T. Lacerda
Employment: Universidade Federal de São Paulo (UNIFESP), Brazil. Research grant: National Counsel of Technological and Scientific Development
(Conselho Nacional de Desenvolvimento Cientíico e Tecnológico - CNPq)***,
Fundação de Apoio à Pesquisa de São Paulo (FAPESP)**, Brazil. Other research grant or medical continuous education:Asta-Zeneca*, Eli-Lilly*, Servier*. Speaker’s honoraria: Eli-Lilly*, Servier*, Abbott*, Glaxo-SmithKline*. Other: Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), UNIFESP; Instituto Sinapse de Neurociências Clínicas, Campinas; Centro de Pesquisa e Ensaios Clínicos Sinapse-Bairral. Itapira, Brazil.
*Modest
**Signiicant
***Signiicant. Amounts given to the authors’ institutions or to a colleague for
research in which the authors has participation, not directly to the author.
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